Dengue virus (DENV) causes dengue fever, the most prevalent arthropod-borne viral illness in humans (NIAID Category A pathogen). Globally, the four serotypes of DENV cause an estimated 100 million new cases of dengue fever and 250,000 cases of dengue hemorrhagic fever (DHF) per year. Currently, no specific therapy is available, and vaccines are still in early stages of development. Given that the most advanced tetravalent live attenuated DENV vaccine candidate showed a poor 30% overall efficacy rate in a recently published phase 2b clinical trial, there remains a pressing need for new approaches for safe, effective vaccines. In the first cycle of this R01 we developed a large panel of ~500 novel monoclonal antibodies (MAbs) against all four DENV serotypes and analyzed the structural, biophysical, and cellular mechanisms of Ab-mediated neutralization of several of them. These studies defined novel epitopes on DENV E proteins recognized by inhibitory antibodies (Abs), many of which are not solvent-accessible according to existing atomic models of the virus particle. Our studies revealed that the structure of DENV was more complex than anticipated and is likely a heterogeneous and structurally dynamic ensemble of different states, each of which may interact differentially with Ab. In this renewal application, we propose to define the spectrum of structural states sampled by the DENV virion, determine the structural basis of differential neutralization of individual DENV serotype by cross-reactive, fusion-loop specific Abs, and assess the role of anti-prM Abs in recognition and neutralization of DENV. This information will be translated into developing a novel inactivated vaccine strategy that traps DENV particles in structural states that preferentially elicit highly neutralizing Abs.